Review
Diverse roles for the LDL receptor family

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Abstract

The low-density lipoprotein (LDL) receptor family consists of several related scavenger receptors that not only function as important cargo transporters, but also inform the cell of changes in its environment by mediating signaling responses. The LDL receptor was the first family member to be characterized and its function seems to be restricted to lipoprotein metabolism. By contrast, lipoprotein metabolism does not appear to be the exclusive function of the other characterized LDL receptor family members. It is now apparent that cargo transport by members of the LDL receptor family is closely associated with regulation of cellular physiology and cellular signaling events. Here, we focus on the diverse biological activities of certain members of this family.

Section snippets

Lessons learned from the LDL receptor

The discovery in 1974 [1] of a cellular pathway for the binding, internalization and degradation of plasma LDL led to the identification of the LDL receptor [2]. This receptor plays a crucial role in the homeostasis of cholesterol by mediating the cellular uptake of apolipoprotein E (apoE)- and apolipoprotein B (apoB)-containing lipoprotein particles. Mutations in the gene encoding the LDL receptor lead to high plasma cholesterol levels and the development of atherosclerotic lesions at an early

Cargo functions of LDL receptor family members

Members of the LDL receptor superfamily display an impressive capacity to transport molecules into the cell. Much of our knowledge regarding the physiological role of these receptors in cargo transport has been derived from the generation of mice deficient in these receptors.

Cytoplasmic adaptor protein binding to LDL receptor family members

Cytoplasmic domains of members of the LDL receptor family interact with an array of intracellular proteins 45, 46 (Table 2). These intracellular proteins are generally classified as adaptor or scaffold proteins and most contain phosphotyrosine-binding domains (PTB) or postsynaptic density 95 (PSD-95)/Disc-large/ZO-1 (PDZ) domains. Many of the identified proteins [such as disabled protein 1 (Dab1), c-Jun N-terminal kinases interacting protein 1 (JIP-1), membrane-associated guanylate kinase 1

Signaling function of LDL receptor family members

Recent studies indicate that certain LDL receptor family members also participate in signaling pathways. This is accomplished by cooperation with additional cell surface molecules that associate directly or indirectly with LDL receptor family members and cytoplasmic adaptor molecules that associate with their cytoplasmic tail.

Conclusions

Cargo transport by members of the LDL receptor family appears to be intimately coupled to the regulation of cellular physiology. Not only is this manifested by regulating levels of certain proteases, lipoproteins and effector molecules, but also by mediating direct cell-signaling responses to ligand binding. Indeed, the growing number of important molecules reported to interact with the cytoplasmic domains of LDL receptor homologs confirms their involvement in several important physiological

Acknowledgements

DKS is supported by grants from the National Institutes of Health (NIH) (HL-50784, HL-65939 and HL-54710). WSA is supported by grant HL61873 from NIH. SLG is supported by grant HL60551 from the NIH and by the Susan G. Komen Breast Cancer Foundation.

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